PROJECT SUMMARY The overall goal of this research project is to develop a test of cerebral vascular function, and provide mechanistic insight into the extent to which the myogenic, neurogenic, and shear-mediated responses contribute to the regulation of the cerebral vasculature. Cerebrovascular disease is the 5th leading cause of death, as well as being a major cause of cognitive impairment and disability in middle-aged to older adults. Understanding the relationship between aging and cerebrovascular function is essential to the development of therapeutic interventions that will improve quality of life and reduce the risk of cerebrovascular events. There are currently no preclinical tools for prediction of future cerebrovascular disease/events in healthy humans; the proposed study aims to address this knowledge gap. The central hypothesis is that our test of ?Cerebral-Vascular Function? will elicit a vasodilatory stimulus, which will be reduced in healthy older subjects, and chronic smokers, and that impairment in these responses will be associated with impaired peripheral vascular regulation and with reduced cerebral vascular reactivity to CO2. A secondary hypothesis is that that blockade of myogenic and neurogenic responses to the ?Cerebral-Vascular Function? test will facilitate assessment of the endothelial shear- stress dependent mechanism of cerebral blood flow regulation. We will address these hypotheses in two broad Specific Aims: 1) assess the responses to the Cerebral-Vascular Function test , and compare responses with a classic test of Cerebral Vascular Reactivity to CO2, and the Peripheral-Vascular Reactivity tests in healthy young subjects, and subjects known to have impaired systemic vascular function, (older healthy subjects, and chronic smokers), and; 2) determine the relative contribution of endothelial-mediated hyperemia from myogenic and neurogenic control of cerebral blood flow. Human subjects will be recruited to address these aims, by adapting the peripheral flow-mediated dilation (FMD) approach of ischemia-reperfusion to the cerebral vasculature by use of lower body negative pressure (LBNP). LBNP (-60 mmHg) will be applied to induce an ?ischemic? stress to the cerebral tissue; rapid release of this stress will elicit shear stress induced cerebral vasodilation. Reactive hyperemia in the intracranial and extracranial arteries will be assessed via calculation of the peak and area under the curve for each response as an index of resistance vessel function. Independently, FMD in the brachial and femoral arteries will be assessed. The rationale for the proposed research is to develop a clinically-relevant test for assessment of cerebral vascular function and identify a mechanism for the previously observed increase in cerebral blood flow to simulated ?ischemia-reperfusion? stress. The approach is innovative as it may provide evidence that cerebral reactive hyperemia is a novel methodological approach and a valid stimulus to assess cerebrovascular function. This contribution is significant as it will provide insight into the detrimental cerebrovascular adaptations that occur with aging, and the overall contribution that endothelial dysfunction may play within this process.